UA82540C2 - Meldonium salts, process of their preparation and pharmaceutical composition based thereon - Google Patents

Abstract

New salts of Meldonium, the method of their preparation, and pharmaceutical formulation on their basis have been described. The general formula of these salts is X-(CH3)3N+NHCH2CH2COOH where X- is an acid anion selected from the group of pharmaceutically acceptable acids. Practically non-hygroscopic and/or increased thermal stability and/or lasting action Meldonium hydrogen salts of fumaric acid, phosphoric acid, oxalic acid, maleic acid, and pamoic acid as well as Meldoinum orotate and galactarate are especially suitable. Novel pharmaceutical formulations containing non-hygroscopic and/or increased thermal stability and/or lasting action 3-(2,2,2-trimethylhydrazinium) propionate salts for oral, parenteral, rectal and transdermal introduction are concurrently described.

Description

Description of the invention

The present invention relates to meldonium salts, 3-(2,2,2-trimethylhydrazine)propionates, which are described by the general formula Х(СНа)ЗМ"МнСНоСНоСООН, where Х' is an acid anion selected from acid phosphate, acid fumarate, acid oxalate, acid maleate and/or acid pamoate, orotate, galactarate, sulfate, dichloroacetate, acid galactarate, fumarate, taurate, maleate, acid aspartate, creatine, acid sulfate, magnesium succinate, acid citrate, citrate, succinate, acid succinate, adipinate, acid tartrate and lactate, which differ from 3-(2,2,2-trimethylhydrazine)propionate dihydrate by its low 70 hygroscopicity and/or increased thermal stability, and/or long-term action. The present invention also relates to the process of obtaining the above-mentioned salts and pharmaceutical compositions containing them. 3-(2,2,2-trimethylhydrazine)propionate was first described in US patent Mo4481218.

It is well known that 3-(2,2,2-trimethylhydrazine)upropionate in the form of dihydrate (this substance is known under the international non-proprietary name of meldonium) is widely used to regulate the ratio t concentrations of carnitine and gamma-butyrobetaine and, therefore, the rate of beta-oxidation of fatty acids in the body

Ioatgoma M., Pieripei E., Kaimipei 1. Miidgopaie: sagaiorgoiesiime asiop (Pgotsdp sagpiiipe-Ioumegipud eiPesi.

Kemiem // Ttepaz Sagaiomazs. May - 2002. - MoI.12, Mob. - R.275-279. Kirr N., 7agaip-Neg2gregd A., Maiivsp V.

Te ve oi ragpia! Tatsyu asii ohidanyop ippiryoge yTog teiyaroiis (tegaru oi apdipa resiogiz apa PNeagi Taishge // Negg, 2002. - MoI.27. Mo7. - R.621-636. Miidgopaye, Mei-88. Ogidv Esh 2001, 26 (1), p .821. 7 Due to these properties, meldonium (registered under the trademark "MI OKOMATYA 9", "MIGOVOMATE 9", "MILDRONAT") is widely used in medicine as an anti-ischemic and anti-stress agent in the treatment of various cardiovascular diseases and other pathologies, where it has site of tissue ischemia |R.S.

Karpov, O.A. Koshelskaya, A.V. Vrublevski, A.A. Sokolov, A.T. Teplyakov, I. Skarda, V. Dzerve, D. Klintsare, A. sch

Vytols, U. Kalnynsh, MY. Kalvynsh, L. Matveeva, D. Urbane. Clinical effectiveness and safety of mildronate in the treatment of chronic heart failure in patients with coronary heart disease. (8)

Cardiology, 2000, volume 6, p.69-74).

However, in the form of dihydrate, meldonium has significant disadvantages, the main of which is its relatively high hygroscopicity. Already after standing at 10095 air humidity for 24 hours, the mass of meldonium due to

The absorption of water increases by 1090, and this substance takes on a syrupy state.

Another significant disadvantage of meldonium is its long half-life, which in humans is 4-10 hours, while it needs to be taken 2-4 times a day | M. Ogegme, Miidgopaiv. RAB "Ohipdekv", 1999, year 1Y; at the same time, it should be noted that experiments on rats showed a longer half-life period |K.

Mozpivie, M. Matotoio, K. Mozpida, M. bZaeki, M. Mipati, M. Evity, M. Kamzhadispi. RNpagtasokipeisz apa S

Bioiodisa! This is 3-(2,2,2-MiteipuIpudgahipisht) rhoriopaie (MET-88), and pome! sagaiorgoyesime adepi, ip so hayiv. Ogyd Megyaroiizt apa Oizrozyop, moi/.28, Mob, 687-694).

Since meldonium dihydrate is not suitable for oral administration once a day, one of the objectives of this invention was to create other pharmacologically acceptable forms of meldonium that would allow for its once-daily administration. It is well-known that betaine salts of amino acids are usually good. in the water. If pharmacologically acceptable acids are selected, the pharmacokinetics of absorption and elimination, as well as the biological activity of these salts, usually do not differ much from these parameters of the original compound. :z" In addition, meldonium is not very stable: when heated, it quickly loses water of crystal hydrate. The anhydrous form of meldonium is also unstable and extremely hygroscopic. In this form, this compound quickly becomes colored and acquires a specific unpleasant smell. Thus, the hygroscopicity and thermal instability of meldonium dihydrate are its significant disadvantages, which limit the possibilities of manufacturing various dosage forms of this compound for oral and external administration. In addition, meldonium dihydrate actively dehydrates already at temperatures of 40-452C. This means that the storage of ready-made medicinal forms of meldonium containing crystalline hydrate is a rather difficult task, especially in countries with a hot climate.

Since the direct use of meldonium dihydrate for the manufacture of oral dosage forms is difficult, the next goal of this invention was to find such pharmacologically acceptable salts of meldonium, which would be devoid of hygroscopicity and/or would be thermally stable and allow them to be stored in any climatic zone for a long time

Pharmacokinetic properties of most meldonium salts practically do not differ from the above-described properties of meldonium itself. Therefore, the use of these salts for the manufacture of pharmaceutical compositions should not have advantages over the use of meldonium itself. (F) But the authors found that the meldonium salts of some pharmaceutically acceptable polybasic acids are a salutary exception in this regard, since, despite their good solubility in water, they differ significantly from meldonium in their pharmacokinetic and pharmacodynamic properties. The unexpected finding of this fact is due to the lack of a theory that could explain why meldonium salts, which dissolve well in water, can differ from meldonium in the rate of resorption and elimination from the body.

Thus, the authors managed to find among the above-mentioned salts some specific meldonium salts with suitable pharmacokinetics and pharmacodynamics, which make it possible to use them once a day. These are 65 compounds described by the general formula Х(СНа)ЗМ"МнСНоСсНоСООН, where Х" is an acid anion selected from monosubstituted fumaric acid, monosubstituted phosphoric acid, monosubstituted oxalic acid, monosubstituted maleic acid, and mono- and/or disubstituted galactaric acid. , pamoic acid and orotic acid.

It is well known that amino acid betaines are usually relatively stable substances. These compounds are good

They occur in water, and the biological activity of their pharmacologically acceptable salts generally does not differ from the biological activity of the original compound.

However, meldonium salts of monovalent, divalent and trivalent pharmaceutically acceptable acids have the same hygroscopicity as meldonium, or even higher than it. Moreover, many of them cannot be prepared in crystalline form, as they form syrups containing different amounts of water. 70 Meldonium salts of both strong and weak acids, namely sulfate, hydrochloride, acetate, lactate, citrate, as well as its salts of many other pharmaceutically acceptable acids are hygroscopic. Therefore, the use of these salts in the preparation of pharmaceutical compositions for oral administration should obviously not have an advantage over the use of meldonium itself.

However, the authors noticed that the meldonium salts of some pharmaceutically acceptable polybasic acids /5 are an exception to this rule and are practically non-hygroscopic, although they are easily soluble in water.

The authors also found that these compounds are very stable when kept for a long time at temperatures from room to 502. Along with this, it was found that such a specific monobasic acid as orotic acid also forms a non-hygroscopic meldonium salt. All the salts claimed by the present invention showed greater thermal stability than that of meldonium.

The bioavailability of meldonium from these salts when administered orally is also good, due to which these salts are much more suitable for the preparation of various dosage forms than the hygroscopic and thermally unstable meldonium. The discovery of this fact was completely unexpected from the point of view of the lack of a theoretical foundation that could explain the difference in the hygroscopicity of meldonium orotate on the one hand and the salts of meldonium polybasic acids, which are also well soluble in water, and on the other hand - its other su with salts

Since these salts are non-hygroscopic and/or have increased thermal stability, they are easily processed and are particularly suitable for the manufacture of solid dosage forms. Aqueous solutions of these salts are less acidic than solutions of the corresponding chlorides. Therefore, these salts are also more suitable for the preparation of dosage forms for administration by injection. at

Below are examples illustrating the process of making salts according to the present invention. These examples do not introduce any limitations to the present invention. -

Example 1 yuyu

The following process can be used to produce salts according to the invention.

Meldonium is dissolved in water or another suitable solvent, an equimolar amount of a polybasic acid selected from fumaric acid, phosphoric acid, aspartic acid, citric acid, lactic acid, maleic acid, oxalic acid or orotic acid is added (the latter is taken in a half-molar amount), and the mixture is stirred at a temperature from 20 to 502 until the formation of the corresponding salt. In the second technological stage, meldonium salts, if necessary, are evaporated to dryness. In the third technological stage, the formed salts, if necessary, are recrystallized from a suitable solvent. "

Example 2 2c Salts according to the invention can also be made from suitable intermediates for the production of meldonium, and, for example, from methyl or ethyl esters of 3(2,2,2-trimethylhydrazine)propionate, where the latter is heated together with the appropriate acids in aqueous or water-alcohol solution, and the subsequent processing, selection and cleaning are carried out in the same way as in the first manufacturing process.

Example C co Process of making a salt from meldonium dihydrate. Meldonium and the corresponding acid are dissolved by stirring in a small amount of water at a temperature of 40-502C. The resulting solution is evaporated in a vacuum at a temperature of 40-502C. Acetone or acetonitrile is added to the resulting mass (which usually has the appearance of a viscous syrup), and the mixture is ground. The precipitated crystalline mass is stirred in acetone or acetonitrile for several hours, filtered, washed with acetone or acetonitrile and dried in a vacuum at room temperature. c The hygroscopicity of the samples was determined by measuring the H 20 content before the test and after 24 hours of exposure in conditions of 10095 humidity (in a closed vessel over water). Under these conditions, meldonium absorbs 1095 of water (in terms of weight gain) within 24 hours. The water content was determined by titration according to the Fisher method; in those cases when syrup was formed, the water content was determined by increasing the weight of the sample.

The claimed invention is illustrated by further examples of salts obtained by means of the above-described iF) processes.

Kz Example 4

Meldonium orotate (1:1). T.pl. 211-214, IN NMR spectrum (020), 5, long.h.: 2.56 (2Н, 6 СНСООО"); 3.29 (2Н, 6 bo SNOM); 3.35 (9Н, 8, MezmМ" ); 6.18 (1H, 8, -«CH-). Experiment, 90: C 43.78; H 6.01; M 18.48. Calculation, 95: C 43.71; H 6.00; M 18.53. The initial HO content in the sample was 0.391995; during 24 hours of exposure at 10096 humidity, it remained unchanged.

Example 5 65 Meldonium phosphate (1:1). T.pl. 158-1602C. Spectrum "H NMR (0-0), 5, pln.h.: 2.60 (2Н, и, СНССОО); 3.31 (2Н, ю,

SNHM); 3.35 (9H, 5, MezM"). Experiment, 90: C 29.64; H 7.05; M 11.33. Calculation, 90: C 29.51; H 7.02; M

11.47. The initial HO content in the sample was 0.076290; during 24 hours of exposure at 10095 humidity, it remained unchanged.

Example 6

Meldonium fumarate (1:1). T.pl. 140-142. INT NMR spectrum, 5 ppm: 2.57 (2Н, 6 СНО); 3.29 (2H, 6CH»o); 3.35 (9H, c, MezmM"); 6.72 (2H, c, -SNASN-). Experiment, 90: C 45.46; H 6.94; M 10.72. Calculation, 90: C 45 .80; H 6.92; M 10.68. The initial HO content in the sample was 0.1896; during 24 hours of exposure at 10090 humidity, it remained unchanged.

Example 7

Meldonium oxalate (1:1). T.pl. 123-125 IN NMR spectrum (029), 6, dln.h.: 2.61 (2Н, 6 СНСОО); 3.30 (2H, i,

ШНЬМ); 3.35 (9H, 5, MezM"). Experiment, 95: C 40.86; H 6.82; M 11.78. Calculation, 96: C 40.68; H 6.83; M 11.86. The initial NO content in the sample was 0.1661905, after 24 hours of exposure at 10095 humidity, it was 3.121195.

Example 8 t Meldonium maleate (1:1). T.pl. 98-1002С0. Spectrum IN YAM (020), 5, dln.h.: 2.60 (2Н, 6 СНСОО); 3.91 (2H, Yu

MSN"); 3.35 (9H, c, MezM"); 6.35 (2H, c, -SNASN-). Experiment, because: C 45.93; H 6.95; M 10.65. Calculation, 90: C 45 .80; H 6.92; M 10.68. The initial content of NoO in the sample was 0.38790; after 24 hours of exposure at 10090 humidity, it was 4.6844905.

Example 9

Meldonium mucate (galactarate; 2:11; хНХО). T.pl. 152-1542S. IN NMR spectrum (020), 6, dln.h: 2.46 (4Н, 5, 2х СН.СОО7 3.26 (4Н, 2хМСН»); 3.35 (18Н, в, 2хМезМ"); 3.98 and 4.31 - two singlets of low intensity, protons of mucous acid. Experiment, for: C 42.13; H 7.58; M 10.77. Calculation, to: C 41.53; H 7.75; M 10, 76.

The initial HO content in the sample was 3.0414965; after 24 hours of exposure at 10095 humidity, it folded. EM 7.6830905. at

Example 10

Meldonium pamoate (1:1; xH»O). Meldonium (5.46 g, 0 mmol) and pamoic acid (5.82 g, 15 mmol) were mixed with water and acetone (15415 ml), the resulting suspension was evaporated, 30-40 ml of toluene was added to the viscous mass that remained, the mass was triturated and repeated evaporation When the residue was not dry enough, the treatment with toluene was repeated. T.pl. 128-1332C (schedule). Spectrum "H NMR (OM5O-dv), 5, rln.h: 2.41 (2Н, 6СНСОО); "Кк 3.14 (2Н, и, СНММ); 3.25 (9Н, в, MezmМ") ; 4.75 (2Н, в, "СНо-(lam3y); 7.12 (2Н, 6 Ni(arom); 7.26 (2Н, y, H(arom)y); 7.77 ою (2нН, a , Naiaromo); 8.18 (2H, a, Naarom); 8.35 (2H, c, Narom.). Experiment, 90: C 62.90; H 5.83; M 4.98. Calculation,

Fo: C 63.07; H 5.84; M 5.07. The initial content of NoO in the sample was 1.7195; after 24 hours of exposure at se 10095 humidity, the mass of the sample increased by 995 due to water absorption. co

Example 11

Meldonium sulfate (2:1). T.pl. 80-1822C (schedule). H NMR spectrum (0-0), 5, pln.h.: 2.60 (4Н, и, 2х СНСООО); 3.30 (4Н, 6, 2хСНоМ); 3.35 (18Н, в, 2хМезМЕ) Experiment, o: C 37.08; H 7.73; M 14.29; 5 8.20. Calculation, 9o:

С 36.91; H 7.74; M 14.35; 5 8,21. The initial HO content in the sample was 0.313905; after 24 hours of exposure « 20 at 10095 humidity, the mass of the sample increased by 11.895 due to water absorption. from c Example 12 c Meldonium dichloroacetate (1:1). T.pl. 86-88eC. Spectrum "H NMR (0-0), 5, pln.h.: 2.61 (2Н, 6 СНСОО); 3.31 i (2Н, 6 СНМ); 3.35 (9Н, в, MezM"); 6.05(1 N, in, -SNSI"). Experiment, 90: C 35,13; H 5.85; M 10,10. Calculation,

Fo: C 34.92; H 5.86; M 10,18. The initial HO content in the sample was 1.1795; after 24 hours of exposure at 10095 humidity, the mass of the sample increased by 1295 due to water absorption. (og) Example 13 t Meldonium mucate (galactarate; 1:1). T.pl. 152-1542S. Spectrum "H NMR (020), 5, pln.h.: 2.47 (2Н, 6 СНСООО)); 3.26 (2Н, 5 СНОМ); 3.35 (9Н, 85, Me»zM"); 3.71 and 3.98 are two singlets of low intensity, protons of sparingly soluble mucoid acid. Experiment, 90: C 40,22; H 6.75; M 7.7595. Calculation, 90: C 40.22; H 6.79; M

F" 50 7.86. The initial HO content in the sample was 1.9895; after 24 hours at 10095 humidity it was 12.895. with Example 14

Mepdonium fumarate (2:1). T.pl. 156-1582S. Spectrum "H NMR (0-0), 5, nln.h: 2.53 (4Н, 6 2хСНа(meld)y); 329 (АН, 2хСНа(meld)); 3.35 (18Н, в, 2хМезМ" ); 6.65 (2H, in, -SNASNU(fum kta)). Experiment, 90: С 46,68; H 7.91; M 13.69. Calculation, 90: C 47.05; H 7.90; M 13.72. The initial content of NO in the sample was 1.513690; after 24 hours (F) of holding at 10095 humidity it was 13.4707905. t Example 15 Meldonium 2-aminosulfonate (taurate; 1:1; x1.5HO). T.pl. 190-1932C; (with decomposition). Spectrum "H NMR 60 (0.0), 6, dln.h.: 2.38 (2Н, 6 СНСООО); 3.18-3.30 (4Н, т, МОНа(meld) 7СНа(Taur)) 3.34 (ZN, z, MezM); 3.42 (2Н,

SNataur)). Experiment, 90: С 32,40; H 8.16; M 13.98; 5 10.60. Calculation, because: C 32.21; H 8.11; M 14.08; 5 10.75. The initial content of NO in the sample was 9.482490; after 24 hours of exposure at 10095 humidity it was 17.0854905.

Example 16 is Meldonium Maleate (2:1). T.pl. 104-106. NMR spectrum of Cya (0290), ppm: 2.54 (4Н, 6СНСОО); 3.30 (4Н, и,

SNOOM); 3.35 (18H, c, MezM"); 6.42 (2H, c, -SNASN-). Experiment, 95: C 46.59; H 7.88; M 13.50. Calculation: C 47.05 ; H 7.90; M 13.72. The initial content of NOO in the sample was 1.359590; after 24 hours of exposure at 10095 humidity, the mass of the sample increased by 1895 due to water absorption.

Example 17

Meldonium I-(H-aspartate (1:11; x2H2O). M.p. 146-1489C. "H NMR spectrum (0-0), 5, pln.h: 2.49 (2H,

SN.SOO); 2.70-2.99 (2H, t, СНа(asp)y) 3.27 (2Н, 6 СНОМ); 3.35 (9H, z, MeziM); 3.95 (1Н, аа, СНМН»). Experiment,

Fo: C 37.71; H 7.85; M 13.03. Calculation, 90: C 38.09; H 7.99; M 13.33. The initial content of HNO in the sample was 12.590; after 24 hours of exposure at 10095 humidity, the mass of the sample increased by 1895 due to 70 water absorption.

Example 18

Meldonium creatine (1:1; хЗН»О). T.pl. 227-2282C (schedule). "H NMR spectrum (0-0), 5, mol.pp.: 2.38 (2Н,

SN.SOO); 3.03 (ZN, 8, MMecreatine)); 3.22 (2Н, 6 СНОМ); 3.35 (9H, in, MezmM"); 3.92 (2H, zv, MSN" (creatine) )- 75 The initial content of NOO in the sample was 15.895; after 24 hours of exposure at 10095 humidity, the mass of the sample increased by 1895 due to absorption water

Example 19

Meldonium sulfate (1:1). T.pl. 98-10090. In NMR spectrum (020), 5, dln.h: 2.62 (2Н, 6 СНСОО); 3.31 (2H, Yu

SNHM); 3.35 (9H, in, MezM"). Experiment, 90: C 29.23; H 6.57; M 11.17; 5 13.10. Calculation: C 29.50; H 6.60; M 11 .47; 5 13.13, The initial HO content in the sample was 1.418995; after 24 hours of exposure at 10095 humidity, the weight of the sample increased by 2095 due to water absorption.

Example 20

Magnesium-meldonium succinate (1:1:1; х2ХО) (see magnesium-meldonium tartrate). T.pl. 135-1409C (schedule). in "H NMR spectrum (0-0), 5, rln.h.: 2.39 (2Н, 6СНСООГ); 2.46 (АН, в, -СНО-СНо- (amber kta)); 222 (2Н , 6 SNOM); s 3.35 (9H, c, MezM"). Experiment, 905: C 36.66; H 7.28; M 8.37. Calculation: C 37.23; H 6.87; M 8.68. The initial (o) content of HNO in the sample was 10.121595; after 24 hours of exposure at 10095 humidity, the mass of the sample increased by 2095 due to water absorption.

Example 21 Fr

Magnesium-meldonium citrate (1:1:1; x2Nos) (see magnesium-meldonium tartrate). T.pl. 195-2002C (schedule). Spectrum "N

NMR (020), 5, dln.h.: 2.48 (2H, 0 SNSOOO/); 2.75 (4H, ad, 2xCHNa(citrus); 3.26 (2H, 6 CHOM); 3.34 (9H, c, MezMM 7). h

Experiment, because: C 36.58; H 6.09; M 6.96. Calculation: C 36.34; H 6.10; M 7.06. The initial content of HO in the sample was 9.4595; after 24 hours of exposure at 10095 humidity, the sample spread.

Example 22 p

Meldonium citrate (1:1). T.pl. 90-9592 (schedule). In NMR spectrum (020), 5, dln.-h: 2.56 (2H, 0, СсНЧСО0 2.85 ШШЧFO (an, aa, 2хСНа(citrus); 3.28 (2Н, 6 СНОМ); 3, 95 (ZN, c, Mezm 7).

Example 23

Meldonium citrate (2:1). T.pl. 101-1072C (schedule). Spectrum "H NMR (0-0), 5, pln.h.: 2.51 (4Н, Her, 2х СНСОО); « 20 2.81 (4Н, ad, 2хСНа(citr3u); 6 2хСНОМ); 3.95 (18Н, в, 2хМезмМ 7. З7З s Example 24

And meldonium succinate (1:1). T.pl. 95-1002C (schedule). Spectrum "H NMR (020), ppm: 2.51 (2Н, и, СНа(meldon.)); "» 2.60 (4Н, 5, -«СНо-СНао- (amber sta); 227 (2Н, 6 СНа(meldon))); 3.35 (9H, 8, MeziM").

Example 25

Meldonium succinate (2:1). T.pl. 103-1072C (cooling). H NMR spectrum (0-0), 5, shln.h: 2.47 (4H, 5 o 2xCH (Meldon.)); 2.59 (AN, c, -СНо-СНо-(vurshtynova std); 229 (4Н, 6 2хСНа(meldon.)); 3.35 (18Н, in, 2хМезиМ")). Example 26

Meldonium adipinate (2:1). T.pl. 110-1149С7 (schedule). Spectrum "TN nMR (020), 6, dln.h: 1.55-1.70 (4H, t, i-y 50 2хСНа(adip)); 2.28-2.39 (4Н, i, 2хСНа( adip)); 2.45 (4Н, 6 2хСНа(meldon)); 3.24 (4Н, 5 2хСНа(meldon.)); 3.34 (18Н, in, ve 2хMesm"). from Example 27

Meldonium tartrate (1:1). T.pl. 100-1072C (schedule). Spectrum "H NMR (0-0), 5, sln.h.: 2.57 (2Н, 6 СНСООО); 3.29 (2Н, 65 СНа(meldon.)); 3.35 (9Н, in, MeziM "); 4.55 (2Н, в, СНвинна кта)у).

Example 28 o Meldonium lactate (1:1). T.pl. 110-1142C (schedule). Spectrum "H NMR (0-0), 5, pln.h.: 1.33-1.48 (ZH, t, Me (milk still ktau! 2.50(2Н, 5 SNСОО ); 3.26 (2Н -

The present invention also relates to pharmaceutical compositions containing at least one of the meldonium salts indicated here as a pharmaceutically active substance and pharmaceutically acceptable solid or liquid fillers that are commonly used in the production of dosage forms. The best are solid compositions suitable for the manufacture of oral dosage forms, as well as syrups and solutions containing salts according to the present invention and fillers.

In cases where the active substance is introduced into tablets, cakes, pills, granules, powders or capsules, 65 they contain meldonium salt in the amount of 0.5 to 5 g per tablet, cake, pill, capsule or per serving of powder or granules.

Below are examples illustrating some embodiments of solid pharmaceutical compositions with salts according to the present invention.

Example 29

Pharmaceutical composition for making tablets:

The meldonium salt according to the present invention is 500 mg

Starch 20 mg

Talc 1Omg 76 Calcium stearate 1mg

Total 5Z1Mg.

Example 30

Pharmaceutical composition for making capsules:

The meldonium salt according to the present invention is 500 mg

Starch bbmg

Talc 26bmg

Calcium stearate Zmg

Total bo2mg.

For the introduction of the active substance by injection or orally in the form of drops, syrup or drink, the pharmaceutical composition contains the meldonium salt according to the invention in an amount from 0.5 to bObo(wt.) and a pharmaceutically acceptable solvent, which can be, for example, distilled water , isotonic solution, glucose solution, buffer solution or their mixture. everything

Below are examples illustrating the implementation of pharmaceutical compositions with salts according to this d) invention for their administration by injection and/or oral route.

Example 31

Pharmaceutical composition for injections: (ав)

Meldonium salt according to this invention 5OOmg "g

Water for injections Bml.

Io)

Example 32

Pharmaceutical composition M form of syrup: with so

Meldonium salt according to this invention 25.00 ml

Methyl p-hydroxybenzoate 0.20-0.60 Og

Propyl-p-hydroxybenzoate 0.01-01 g

Propylene glycol 6.15-8.30 g

Sorbitol 120.00-150.50 g Glycerin 10.00-15.00 g Purified water 108 ml » Total 25 Oml.

For transdermal administration of the active substance, its content is in a cream, gel, solution, ointment or patch

Go! is 0.5-4096 (mass).

Below is an example illustrating the implementation of a pharmaceutical composition with salt according to the present invention for its introduction through the skin (locally or topically). Example 33 2» 50 Pharmaceutical composition in the form of a gel:

Meldonium salt according to the present invention is 10.0095

Sho Sodium starch glycolate type C 4.00

Propylene glycol 2.00

Fumaric acid 0.40

Purified water 83.40. and For rectal administration of salts according to this invention, their content in a suppository or microenema is from 0.5 to 409 (wt). for

Claims (14)

The formula of the invention 1. Meldonium salts corresponding to the general formula: X'(СНа)Z.М"МнНСнНСнННСОоОон 65 where X' is an anion selected from the group consisting of dihydrophosphate, hydrofumarate and orotate anions. 2. The salt according to claim 1, which is meldonium dihydrogen phosphate. Z. The salt according to claim 1, which is meldonium hydrofumarate. 4. The salt according to claim 1, which is meldonium orotate. 5. The method for obtaining meldonium salts according to any of claims 1-4, in which: (a) dissolving meldonium corresponding to the formula 3-(2,2,2-trimethylhydrazine)propionate in a known manner in water or another suitable solvent ; (B) adding an equimolar amount of a polybasic acid selected from fumaric acid, phosphoric acid and orotic acid; (c) stirring the mixture at a temperature from 20 to 50 9C until the formation of the corresponding salt; if necessary, evaporation of the formed meldonium salt to dryness; and, optionally, recrystallization from a suitable solvent. 6. A pharmaceutical composition containing one of the salts according to any one of claims 1-4 as an active ingredient, and intended for oral or sublingual administration in the form of coated or uncoated tablets, capsules, cakes, dragees, granules, powder or solution , where the specified composition contains from 0.5 to 5 g of the active 7/5 ingredient in each tablet, capsule, dose of granules or powder, or in each dragee, or is a 0.5-40 9o (wt.) solution or syrup for oral administration. 7. Pharmaceutical composition according to claim 6, where the pharmaceutically acceptable carrier is selected from the group consisting of one or more of the following members: stearic acid and its salts, lactose, glucose, sucrose, starch, talc, vegetable oils, polyethylene glycols, microcrystalline cellulose, aerosol , flavoring agent, flavor correctors, dyes, ethyl alcohol and water. 8. A pharmaceutical composition that contains one of the salts according to any one of claims 1-4 as an active ingredient and is intended for parenteral administration in the form of a solution for injections, where said composition contains from 0.5 to 40 95 (wt.) active ingredient and a pharmaceutically acceptable solvent. 9. Pharmaceutical composition according to claim 8, where the pharmaceutically acceptable solvent is selected from the group consisting of one or more of the following members: distilled water, isotonic solution, buffer solution and glucose solution. at 10. A pharmaceutical composition that contains one of the salts according to any of claims 1-4 as an active ingredient and is intended for transdermal administration in the form of an ointment, cream, gel, solution or patch, where said composition contains from 0.5 to 40 95 (wt.) of the active ingredient and a pharmaceutically acceptable carrier. at 11. Pharmaceutical composition according to claim 10, where the pharmaceutically acceptable carrier is selected from the group consisting of one or more of the following members: water, polyethylene glycols 400, 1500 and 4000, vegetable oils, fats, glycerin, preservatives, emulsifiers, stabilizers, porous polymer material, dimethyl sulfoxide, alcohol and water. 12. A pharmaceutical composition that contains one of the salts according to any of claims 1-4 as an active ingredient and c 335 is intended for rectal administration in the form of suppositories or microclyzes, and the specified composition c contains from 0.5 to 40 95 (wt. ) of the active ingredient and a pharmaceutically acceptable carrier. 13. Pharmaceutical composition according to claim 12, where the pharmaceutically acceptable carrier is selected from the group consisting of one or more of the following members: water, polyethylene glycols 400, 1500 and 4000, vegetable oils, fats, glycerin, preservatives, emulsifiers and stabilizers. " 14. Meldonium salts according to any one of claims 1-4, which are intended for the manufacture of a pharmaceutical composition for oral administration once a day. ;" Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 8, 25.04.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. so ko 1 of them 50 s2 F) ko 60 b5